PROJECT SUMMARY: The broad, long-term objective of this proposal is to understand how cancer evades and disarms the immune system at the molecular, cellular and organism level so this process can be interrupted for the successful treatment of cancer with monoclonal antibody (mAb) therapy. In the past 4.5 years, members of Project 3 have worked interdependently with other members of this P01 to produce 51 collaborative publications and accrue over 800 patients to therapeutic clinical trials that have directly emanated from our P01. Importantly, we have created impact in that we have advanced our understanding of mAb therapy for cancer and have introduced new reagents in man whose efficacy likely depends on the innate immune system. This P01 competitive renewal application continues to primarily investigate the human innate immune system and Project 3, while integrated with the efforts of Projects 1, 2 and 4, is focused on natural killer (NK) cells. During the past five years it has become clear that: 1) the affinity of the Fc receptor (R) for the Fc fragment of mAb can predict clinical outcome in the mAb therapy of certain cancers; 2) elimination of T regulatory (Treg) cells can enhance cytotoxic T cell adoptive therapy in patients with chemoresistant cancer; 3) blockade of CTLA-4, an inhibitory ligand on cytotoxic T cells, can improve survival in patients with melanoma; 4) avoiding the interaction of the killer immunoglobulin-like receptor (KIR) with its MHC Class I ligand, the NK cell can enhance long term survival in T cell depleted HLA-haploidentical bone marrow transplant for acute myeloid leukemia. We hypothesize that a better understanding of NK cell FcR expression and of NK cell tolerance will allow us to improve the outcome of cancer patients treated with mAb therapy. In the coming cycle, we will work to understand how developing NK cells acquire FcyRlll (CD16) on their cell surface and assess whether this process results in improved antibody dependent cellular cytoxicity (ADCC). Next we will characterize negative regulators of NK cell ADCC in an effort to block these and enhance ADCC of cancer. Finally, we will perform two Phase l/ll trials that will block the inhibitory KIR in an attempt to enhance tumor killing in man, one in combination with an anti-CD20 mAb for the treatment of lymphoma. The work outlined for Project 3 will be interdependent on Projects 1, 2 and 4 as well as Cores A, B, and C When completed, it will provide new insights as to how NK cells may be modulated in order to improve ADCC with mAb therapy in man. We expect our work to result in an improvement in disease free survival for cancer patients following the administration of mAb therapy.